Obesity is a condition of an excessive accumulation of energy in the body, in which the natural energy reserve, stored in the fatty tissue of humans and other mammals, is increased to a point where it is associated with certain health conditions or increased mortality. Obesity develops from an imbalance between energy expenditure and energy intake, and the physiological approach to obesity treatment is to achieve a negative energy and fat balance. Indeed the weight loss through diet is effective for the majority of patient yet very few manage to maintain their initial weight loss over the long time.
Obesity has reached epidemic proportions globally, with more than 1.6 billion adults overweight—at least 400 million of them clinically obese—and is a major contributor to the global burden of chronic disease and disability (WHO fact sheet, 2006). WHO further projects that by 2015, approximately 2.3 billion adults will be overweight and more than 700 million will be obese. At least 20 million children under the age of 5 years are overweight globally in 2005. Obesity and overweight pose a major risk for serious chronic diseases, including type-II diabetes, cardiovascular disease, hypertension, dyslipidemia, metabolic syndrome, stroke, and certain forms of cancer. The health consequences range from increased risk of premature death, to serious chronic conditions that reduce the overall quality of life.
Although obesity has long been associated with serious health issues, it has only recently been regarded as a disease in the sense of being a specific target for medical therapy. Consequently, developing obesity treatments that target novel pathways is a growing focus for both biopharmaceutical and the medical device industries (Melnikova I. & Wages D Nature Reviews Drug Discovery (2006); 5: 369-370).
The available therapies for treatment of obesity have proved to be of limited value either due to inadequate efficacy or due to higher rate of adverse effects and hence there exists a need for better approach with desired efficacy having low side effects.
Many of the compounds using various new therapeutic approaches such as NPY receptor antagonist, beta3 agonist etc. are in early stage of development. Recently selective thyroid receptor ligands are also being explored for the treatment of obesity.
Epidemological evidences clearly reveal the relationship between the altered carbohydrate and lipid metabolism, accumulation of body fat and cholesterol and subsequent risk of cardiovascular diseases such as atherosclerosis, hypertension etc. Atherosclerosis, a disease of the arteries, is considered to be a leading cause of death worldwide. Epidemiological evidence has clearly established hyperlipidemia as a primary risk factor leading to cardiovascular disease due to atherosclerosis. In recent years, medical fraternity have placed renewed emphasis on lowering plasma cholesterol levels, and more particularly low density lipoprotein cholesterol as an essential step for prevention of cardiovascular diseases. The upper limits of “normal” are now known to be significantly lower than heretofore appreciated. As a result, large segments of populations are now realized to be at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is more prevalent among diabetic subjects, at least in part due to the existence of multiple independent risk factors in this population. Successful treatment of dyslipidemia in the general population, and diabetic subjects in particular, is therefore of utmost clinical importance.
Hypertension is a condition that occurs in the human population as a secondary symptom to various other disorders. However, hypertension is also evidenced in many patients in whom the causative factors are unknown. While such “essential” hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders has not been well established. Many patients also display the symptoms of high blood pressure in the complete absence of any other signs of disease or disorder. It is known that hypertension can directly lead to various complications such as heart failure, renal failure and stroke (brain hemorrhaging). Hypertension can also contribute to the development of atherosclerosis and coronary disease. Hypertension rarely manifests alone but usually clusters with other cardiovascular risk factors, such as insulin resistance, visceral obesity, and dyslipidemia. These conditions gradually weaken a patient and can lead to death. Though effective blood pressure control is generally regarded as the most important intervention to reduce long-term complications of hypertension the treatment guidelines are now beginning to incorporate the concept of global cardiovascular risk management to improve patient outcomes.
Metabolic syndrome, a cluster of metabolic abnormalities is a combination of insulin resistance, dyslipidemia, obesity and hypertension, which leads to increased morbidity and mortality by cardiovascular diseases (CVD). In the general population, metabolic syndrome increases the risk for CVD by a factor of 1.65. The presence of metabolic syndrome predicted an increased risk for total and cardiovascular mortality (Eberhard Ritz, Am. J Cardiol (2007); 100 [Suppl]: 53-60). In one of the study it is estimated that metabolic syndrome is present in more than 20% of US adult population. (Young-Woo Park et al. Arch intern Med (2003); 163: 427-436)
In type-II diabetes, obesity and dyslipidemia are also highly prevalent and around 70% of people with type 2 diabetes additionally have hypertension once again leading to increased mortality of cardiovascular diseases.
Metabolic disorders that affect glucose and lipid metabolism such as hyperlipidemia, obesity, diabetes, insulin resistance, hyperglycemia, glucose intolerance, and hypertension have long term health consequences leading to chronic conditions including cardiovascular disease and premature morbidity. Such metabolic and cardiovascular disorders may be interrelated, aggravating or triggering each other and generating feedback mechanisms, which is still unclear.
Hence, multifactorial intervention is crucial in the prevention of type-II diabetes and the reduction of global cardiovascular risk associated with metabolic syndrome. (Richard Ceska, Diabetes and Vascular Disease Research (2007); 4 (suppl): S2-S4) Moreover, multifactorial intervention has proved more beneficial than reducing individual risk factor for global cardiovascular risk reduction. Currently, there is no single treatment available which simultaneously addresses multiple components of metabolic syndrome.
Thyroid gland in response to stimulation by TSH, produces T4, T3 and rT3. Although T4, T3 and rT3 are generated within the thyroid gland, T4 is quantitatively the major secondary product. Production of T3 & rT3 within the thyroid is regulated to very small quantities and is not considered significant compared to peripheral production. T4 is either converted to T3 or rT3, or eliminated by conjugation, deamination or decarboxylation. It is estimated that more than 70% of T4 produced in thyroid is eventually deiodinated in peripheral tissues to form T3 or rT3. Although some T3 is produced in the thyroid, approximately 80-85% is generated outside the thyroid, primarily by conversion from T4 in liver and kidney. Further degradation of T3 & rT3 results in the formation of several distinct diiodothyronines: 3,5-T2, 3,3′-T2 and 3,5′-T2 (Kelly G S. Altern Med Rev (2000); 5(4): 306-333). Structurally all thyroid hormones can be divided into two ring i.e. prime ring and non-prime ring and its SAR suggests unpredictable behaviour of the effect of substituents at (3′-, 5′-, 3- and 5-) on the prime and non-prime ring respectively (Burger' 6th edition, vol 3, pp. 564-565). T3 is considered to be the most metabolically active thyroid hormone. Various experimental evidences suggest that major effects of thyroid hormone are mediated by T3. Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, the metabolic rate, body temperature, and mood, and influence serum low density lipoprotein (LDL) levels. Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety (WO200703419). The brain is also an important target of thyroid hormone, mainly during development but also in adult animals. Severe neonatal hypothyroidism is associated with alterations in cerebellum, especially on granular and Purkinje cells, which exhibit impaired differentiation and migration; Purkinje cells are hypoplastic, and the granular cells fail to migrate from the external germinal layer to the internal granular layer adequately.
Interestingly, it is known that the thyroid hormone known as thyroxine (“T4”) converts to thyronine (“T3”) in human skin by deiodinase I, a selenoprotein. Selenium deficiency causes a decrease in T3 levels due to a decrease in deiodinase I activity; this reduction in T3 levels is strongly associated with hair loss. Consistent with this observation, hair growth is a reported side effect of administration of T4. Furthermore, T3 and T4 has been the subject of several patent publications relating to treatment of hair loss, including, for example, International Patent Application Publication No. WO 00/72810, and WO00/72811,
The use of thyroid hormones is currently limited as a replacement therapy for patients with hypothyroidism. However, replacement therapy, particularly in older individuals is limited by certain adverse effects of thyroid hormones. Some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders, if adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, cholesterol lowering to treat hyperlipidemia, amelioration of depression and stimulation of bone formation in osteoporosis (Liu Ye et al., JMC (2003); 46: 1580-88) It has been found that hyperthyroidism is associated with low total serum cholesterol, which is attributed to thyroid hormone increasing hepatic LDL receptor expression and stimulating the metabolism of cholesterol to bile acids (Abrams J J et. al. J. Lipid Res. (1981); 22: 323-38). Hypothyroidism, in turn, has been associated with hypercholesterolemia and thyroid hormone replacement therapy is known to lower total cholesterol (Aviram M. et. al. CUn. Biochem. (1982); 15: 62-66; Abrams J J et. al. J. Lipid Res. (1981); 22: 323-38). Thyroid hormone has been shown in animal models to have the beneficial effect of increasing HDL cholesterol and improving the ratio of LDL to HDL by increasing the expression of apo A-I, one of the major apolipoproteins of HDL (Ness G C. et. al. Biochemical Pharmacology, (1998); 56: 121-129; Grover G J. et. al. Endocrinology, (2004); 145: 1656-1661; Grover G J. et. al. Proc. Natl. Acad. Sci. USA, (2003); 100:10067-10072). Through its effects on LDL and HDL cholesterol, it is possible that thyroid hormones may also lower the risk of atherosclerosis and other cardiovascular diseases. Additionally, there is evidence that thyroid hormones lower Lipoprotein (a), an important risk factor which is elevated in patients with atherosclerosis (Paul Webb. Expert Opin. Investig. Drugs, (2004); 13(5): 489-500; de Bruin et. al. J. CUn. Endo. Metab., (1993); 76: 121-126).
Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and in particular by cardiovascular toxicity (Thyrotoxicosis) (Liu Ye et al., JMC (2003); 46: 1580-88).
Thyroid hormone exerts there effects through thyroid receptors. There are two major subtypes of thyroid receptors located within the nucleus (Genomic effect) TRα and TRβ. TRα1, TRβ1 and TRβ2 isoforms bind thyroid hormone and acts as a ligand regulated transcription factors. The TRα2 isoform is prevalent in pituitary and other parts of the CNS, does not bind thyroid hormones and acts in many context as a transcriptional repressor. TRα1 is also widely distributed. The literature suggests many or most effects of thyroid hormones on the heart, and in particular heart rate and rhythm are mediated through the TRα1 isoform. On the other hand, most actions of the hormones on the liver and other tissues are mediated more through the β forms of receptors (Liu Ye et al., JMC (2003); 46: 1580-88).
Thyroid hormone has been demonstrated to modulate the behavior of many metabolic pathways potentially relevant for the basal metabolic rate. In general terms, the major candidate mechanisms include uncoupling of cellular metabolism from adenosine triphosphate (ATP) synthesis, or changes in the efficiency of metabolic processes downstream from the mitochondria. Therefore efforts have been made to synthesize thyroid hormone beta selective and/or tissue selective compounds for the treatment of metabolic disorders, which are devoid of thyrotoxic side effects mediated by TRα receptors.
Thus in effort to make specific TRβ selective Thyroid ligands many researchers have tried to synthesize Thyroid mimetics wherein the effect of various prime and non-prime rings and the substituents on it are studied as disclosed in US20050085541, US20040039028, WO2007003419, WO2006128056, WO200709913, US20010051645, US20020049226 and US20030040535 all of which are incorporated herein as reference.
Until recently, T3 was found to be more biologically active than T4 and is presently thought to be the predominant activator of the thyroid hormone receptors (Burger' 6th edition, vol 3, pp. 564-565). In the last decade or so, evidence has accumulated that naturally occurring iodothyronines other than T3 exerts biological effects. Among these, 3,5-diiodothyronine appears to be responsible for rapid, short-term effects on cellular oxidative capacity and respiration rate by direct interaction with mitochondrial binding sites. The accumulated evidence permits the conclusion that the action of T2 do not simply mimic those of T3 but instead are specific action exerted through mechanism that are independent of those actuated by T3 through thyroid hormone receptors (A. Lombardi. Immun Endoc and Metab Agents in Med Chem (2006); 6: 255-65; WO200509433).
Growing body of evidences now suggest that, 3,5-diiodothyronine can induce metabolic inefficiency, possibly by stimulating energy loss via mechanism involving the mitochondrial apparatus rather that nuclear receptors. Such an action of T2 can potentially result in a reduced adiposity and less body weight gain without inducing a clinical syndrome related to thyrotoxic state, by increasing fatty acid influx in to mitochondria and fatty acid oxidation (A. Lombardi. Immun Endoc and Metab Agents in Med Chem (2006); 6: 255-65; Horst C., Biochem J. (1989); 261: 945-950). From a clinical point of view a scenario involving high level of fatty acid oxidation, reduced fat storage, reduction in serum triglyceride and cholesterol levels, reduced lever steatosis, reduced body weight gain without a reduction in calorie/fat intake is an attractive prospect for an intractable obesity (A. Lombardi. Immun Endoc and Metab Agents in Med Chem (2006); 6: 255-65).
WO2005/009433 discloses the composition of 3,5 T2 in therapeutically effective doses mainly for use in obesity, hepatic steatosis and dyslipidemia.
In summary, Thyroid hormones and other idothyronine together or individually influence the metabolism of virtually every cell of the body. These hormones has important physiological role such as to maintain body weight, the metabolic rate, body temperature, and mood, and influence serum low density lipoprotein (LDL) levels etc. Thus, thyroid hormones (T4, T3) can cause weight reduction via increased metabolic rate and a LDL cholesterol reduction through both an upregulation of LDL receptors and increased cholesterol metabolism. However thyroid hormone do not have sufficiently broad therapeutic window, particularly with regard to cardiac acceleration, to be useful for treatment of disorders such as obesity and lipid disorders. Very recently it has been reported that TRIS selective agonists might be exploited as a therapeutically effective means to lower weight and plasma cholesterol without eliciting deleterious cardiac effects. However, recently it has also been found that the TRβ selective agonist induce proliferative response like lead to hepatocyte proliferation and also induced pancreatic acinar cell proliferation (Amedeo columbano. Endocrinology (2006); 147(7): 3211-8). There are also reports that T3 increases food consumption at low dosage in animal, independent to its nuclear effects (Wing May Kong et al. Endocrinology (2004); 145: 5252-5258) and the increase in energy intake were also displayed by T2, (Horst et al., J Endocrinology (1995); 145: 291-297) which can be compensatory in the treatment of obesity.
Thus, there exists a need for novel thyroid like compounds, which are useful for the treatment of metabolic disorders such as obesity, insulin resistance, diabetes, dyslipidemia, fatty liver, metabolic syndrome, and disorders of altered thyroid function without having undesirable effects such as thyrotoxicosis and increase in food consumption.
Accordingly, inventors of the present invention have found novel thyroid like compounds which are expected to demonstrate a utility for the treatment or prevention of diseases or disorders associated with inappropriate thyroid hormone activity, for example: 1) The condition associated with a disease or disorder associated with excessive fat accumulation, altered mitochondrial function 2) obesity 3) lipid disorders caused by an imbalance of blood or tissue lipid levels such as dyslipidemia, atherosclerosis 4) impaired glucose tolerance 5) type II diabetes 6) replacement therapy 7) depression 8) cardiovascular diseases and 9) skin disorders and significantly devoid of undesirable effects like thyrotoxicosis and increase in food consumption.
WO2007027842 relates to an anilinopyrazole compounds useful for the treatment of diabetes and related disorders. US2004110816 discloses certain reverse transcriptase inhibitors of pyrazole derivatives useful for the treatment of HIV and WO9716422 discloses certain chromanyl and thiochromanyl compounds having retinoid like activity.